The hippocampus of the mammalian brain, and particularly the dentate regions with its various inter-connections, are now recognized as playing key roles in both normal and pathological brain functions. The dentate gyrus, as the primary "relay" for cortical input to the hippocampus, processes information critical to complex behaviors such as learning and memory. The activity and integrity of dentate neuronal populations may also set the level of excitability in the limbic system; maximal activation of dentate neurons facilitates spread of seizure activity, and dentate cell loss and/or axonal reconnectivity has been implicated in various animal models of epileptogenesis as well as in human epilepsy. Finally, studies of the connectivity and receptor populations of hippocampus have begun to implicate this limbic structure in a variety of issues relevant to affective disorders. Given these roles, it seems particularly important to elucidate the local connections of the hippocampal/dentate region and to examine its responses to modulatory substances. Over the past several years, we have attempted to characterize the properties and connectivities of some of the hippocampal interneuron populations. We propose to continue that analysis, with a particular focus on the pathways of interaction between the dentate and pyramidal cell regions. Our work has suggested that far from being a simple relay between entorhinal cortex and Ammon's horn, the dentate gurus has complex circuitry and a large number of cell types with unique characteristics. These observations add to studies from other laboratories which show the dentate gurus to be one among the "hot spots" in the brain for receptors to potential modulatory substances. Changes in circulating steroid hormone levels has been shown to affect the integrity of the granule cells and their targets in CA3 neurotrophic factors and their receptors have now been found in these neurons; and mRNAs for a variety of factors can be altered as a function of electrical activities. Despite these findings, relatively little is known about how neuromodulatory substances, such as hormones or neurotrophins, affect dentate function. We propose to continue our elucidation of hippocampal circuitry, and to examine the direct affects of steroid hormones, neurotrophins and other potential modulatory substances on granule cells, and on granule cell synaptic transmission to dentate hilar and CA3 pyramidal cells. We will focus on circuits and drug actions that are likely to be significant for tissue plasticity, excitability, and viability. Electrophysiological recording and optical imaging, complimented by electron microscopy and immunocytochemistry, will be employed in these attempts to shed some light on the pathways of information transfer through the dentate, and on the processes by which that transfer can be modulated.